The babies of women with diabetes are two to five times more likely to develop birth defects than offspring of women without the disease.
A recent study in animals by scientists at Joslin Diabetes Center in Boston helps explain why. The research, appearing in the October issue of the American Journal of Physiology: Endocrinology and Metabolism, suggests that high blood glucose levels early in pregnancy deprive the embryo of oxygen, interfering with its development.
"Until recently, it was not understood how diabetic pregnancy could cause birth defects. My laboratory wanted to explore this research because the more we know about the effects of the mother's diabetes on the embryo, the more tools we have to identify therapies that may prevent birth defects in diabetic pregnancy," says the study's lead investigator, Mary R. Loeken, Ph.D., an investigator in Joslin's Section on Developmental and Stem Cell Biology and Assistant Professor of Medicine at Harvard Medical School.
Women with both type 1 and type 2 diabetes run a high risk of having babies with birth defects, especially of the heart and spinal cord. Because these organs form during the first few weeks of pregnancy, coinciding with the time that a woman may first learn she is pregnant, aggressive control of blood glucose levels just before and after conception is critical. "Women with diabetes should be consulting with their healthcare team to be sure they have good glycemic control before becoming pregnant," says Dr. Loeken. Maintaining blood glucose control continues to be important throughout the pregnancy, but it is particularly important during the first eight weeks, when an embryo's organs are forming.
In addition to recommending that women with diabetes have good control of their glucose levels before becoming pregnant, Dr. Loeken recommends that obese women who don't know if they have diabetes but who are planning to become pregnant be tested for diabetes. There have been several recent reports of increased birth defects in the pregnancies of obese women. "Many obese individuals have type 2 diabetes and do not know it, so it is a good idea to bring glucose levels to within the normal range before becoming pregnant, and to monitor women with pre-diabetes closely during pregnancy to make sure that they don't develop diabetes," Dr. Loeken says.
In the new study, Dr. Loeken and her colleagues examined embryos of pregnant mice injected with glucose (the sugar that is elevated in the blood during diabetes) to mimic diabetic pregnancy. The researchers knew that oxygen is needed by cells to break down glucose and produce energy, and that normally, when oxygen is consumed, more oxygen is delivered to tissues by increasing blood flow to those tissues. However, at the stage of embryonic development in which birth defects in women with diabetes frequently are believed to occur, the embryo does not yet have a heart or blood supply, and so the scientists theorized it might not be possible to replace oxygen as rapidly as it is consumed. This has the potential to cause hypoxic stress, or damage to cells caused by low oxygen (hypoxia).
Working in collaboration with Peter Smith, Ph.D., Director of the BioCurrents Research Center at the Marine Biological Laboratory at Woods Hole, Mass., Dr. Loeken found that the oxygen concentrations in embryos of mice injected with glucose were significantly lower than in control embryos. This demonstrated that breaking down higher amounts of glucose caused oxygen to be used up faster than it could be delivered.
The researchers then injected pregnant mice with glucose, or exposed them to varying levels of oxygen to see if raising and lowering oxygen delivery to the embryos had the same effect as raising and lowering glucose. The scientists' goal was to see whether oxygen deprivation is what mediates the effects of high glucose on the embryo in pregnant diabetic mice. Dr. Loeken's lab had previously found that inducing high blood glucose levels in pregnant mice suppressed Pax3 expression in embryos. Pax3 is a gene required for healthy formation of the brain and spinal cord.